60798-07-4Relevant academic research and scientific papers
Discovery of novel inhibitors of human phosphoglycerate dehydrogenase by activity-directed combinatorial chemical synthesis strategy
Zhou, Xia,Tan, Yuping,Gou, Kun,Tao, Lei,Luo, Yuan,Zhou, Yue,Zuo, Zeping,Sun, Qingxiang,Luo, Youfu,Zhao, Yinglan
, (2021/07/26)
Serine, the source of the one-carbon units essential for de novo purine and deoxythymidine synthesis plays a crucial role in the growth of cancer cells. Phosphoglycerate dehydrogenase (PHGDH) which catalyzes the first, rate-limiting step in de novo serine biosynthesis has become a promising target for the cancer treatment. Here we identified H-G6 as a potential PHGDH inhibitor from the screening of an in-house small molecule library based on the enzymatic assay. We adopted activity-directed combinatorial chemical synthesis strategy to optimize this hit compound. Compound b36 was found to be the noncompetitive and the most promising one with IC50 values of 5.96 ± 0.61 μM against PHGDH. Compound b36 inhibited the proliferation of human breast cancer and ovarian cancer cells, reduced intracellular serine synthesis, damaged DNA synthesis, and induced cell cycle arrest. Collectively, our results suggest that b36 is a novel PHGDH inhibitor, which could be a promising modulator to reprogram the serine synthesis pathway and might be a potential anticancer lead worth further exploration.
Synthesis, crystal structure and evaluation of cancer inhibitory activity of 4-[indol-3-yl-methylene]-1H-pyrazol-5(4H)-one derivatives
Jing, Lingling,Wang, Liang,Zhao, Yinglan,Tan, Rui,Xing, Xiumei,Liu, Ting,Huang, Wencai,Luo, Youfu,Li, Zicheng
, p. 691 - 696 (2013/02/23)
A series of 4-(1H-indol-3-yl-methylene)-1H-pyrazol-5(4H)-one derivatives have been synthesised. The Z structure of 4-[(1-methyl-1H-indol-3-yl)methylene]- 3-phenyl-1-p-tolyl-1H-pyrazol-5-one was determined by X-ray crystallography. The antitumour activity was evaluated against five cancer cells by MTT assay. [(1H-Indol-3-yl)methylene]-1-(2,4-dinitrophenyl)- 3-methyl-1H-pyrazole-5-one and 4-{4-[(1-benzyl-1H-indol-3-yl)methylene]-3-methyl-5-oxo-4,5-dihydro-1Hpyrazol- 1-yl}-benzoic acid have similar anticancer activity with 5-UF on the test cancer cells (exception of A375). Almost all the target compounds displayed antitumour activity against A549 and PC-9, and those with benzyl at 1- position of indole had higher activity against PC-9 (IC50 value lower than 30 μM). Those with benzyl at the indole and carboxyl at the phenyl part of of pyrazole were more active against PC-9 and A549 cells, providing a good indication for subsequent optimisation as lung cancer inhibitory agents.
Discovering potent inhibitors against c-Met kinase: Molecular design, organic synthesis and bioassay
Liang, Zhongjie,Ding, Xiao,Ai, Jing,Kong, Xiangqian,Chen, Limin,Chen, Liang,Luo, Cheng,Geng, Meiyu,Liu, Hong,Chen, Kaixian,Jiang, Hualiang
experimental part, p. 421 - 430 (2012/02/05)
The receptor tyrosine kinase c-Met is an attractive target for therapeutic treatment of cancers nowadays. The discovery of small molecule inhibitors is of special interest in the blockade of the c-Met kinase pathway. Here, we initiated our study from comp
Virtual ligand screening of the p300/CBP histone acetyltransferase: Identification of a selective small molecule inhibitor
Bowers, Erin M.,Yan, Gai,Mukherjee, Chandrani,Orry, Andrew,Wang, Ling,Holbert, Marc A.,Crump, Nicholas T.,Hazzalin, Catherine A.,Liszczak, Glen,Yuan, Hua,Larocca, Cecilia,Saldanha, S. Adrian,Abagyan, Ruben,Sun, Yan,Meyers, David J.,Marmorstein, Ronen,Mahadevan, Louis C.,Alani, Rhoda M.,Cole, Philip A.
scheme or table, p. 471 - 482 (2011/08/06)
The histone acetyltransferase (HAT) p300/CBP is a transcriptional coactivator implicated in many gene regulatory pathways and protein acetylation events. Although p300 inhibitors have been reported, a potent, selective, and readily available active-sitedirected small molecule inhibitor is not yet known. Here we use a structure-based, in silico screening approach to identify a commercially available pyrazolone- containing small molecule p300 HAT inhibitor, C646. C646 is a competitive p300 inhibitor with a Ki of 400 nM and is selective versus other acetyltransferases. Studies on site-directed p300 HAT mutants and synthetic modifications of C646 confirm the importance of predicted interactions in conferring potency. Inhibition of histone acetylation and cell growth by C646 in cells validate its utility as a pharmacologic probe and suggest that p300/CBP HAT is a worthy anticancer target.
